[0001] The present invention relates to substituted imidazole derivatives and their non-toxic,
pharmaceutically acceptable acid addition salts, and their preparation, and to pharmaceutical
compositions containing the same.
[0002] Known compounds possessing antihypertensive properties can be grouped, according
to their pharmacological mechanism, as follows:
1. Diuretics, e.g., tienilic acid (U.S. Patent 3,758,606), metolazone (U.S. Patent
3,360,518) and bumetadine (U.S. Patent 3,634,583);
2. Stimulants of central a-adrenergic receptors, e.g., clonidine (U.S. Patent 3,202,660),
imidazole derivatives [Jen et al, J. Med Chem. 18 (1975), 90], guanabenz (German OLS
1,802,364), BS 100-141 (French Patent 1,584,670), tiamenidine (German OLS 1,941,761),
guanazodine (British Patent 1,216,096) and guanethidine (U.S. Patent 2,928,829);
3. a-Adrenergic blocking agents, e.g., prazosin (U.S. Patent 3,511,836);
4. A-Adrenergic blocking agents, e.g. propanolol (U.S. Patent 3,337,628) and metoprolol
(German Patent 2,106,209);
5. Dopamine-β-hydroxylase inhibitors, e.g., bupicomide (German OLS 2,217,084);
6. Norepinephrine-depleting drugs, e.g., MJ 10459-2 [Mathier et al, J. Med. Chem.
16 (1973) 901];
7. Inhibitors of the renin-angiotensin system, e.g., saralasine (German Patent 2,127,393);
and captopril (Svensk Farm. Tidskr. 83 (1979) 71); and
8. Peripheral vasodilators, e.g., minoxidil (U.S. Patent 3,644,364).
[0003] Of 4-substituted arylalkylimidazole derivatives related to the compounds of this
invention only 4-[2-(phenyl)-ethyll-imidazole [C.A. 56:14256a, C.A. 60:14495e) and
4-[2-(3',4'-dimethoxyphenyl)-ethyl]-5-methyl-imidazole (C.A. 74:142135z) have been
previously described. However the prior art does not disclose any pharmaceutical utility
for these compounds.
[0004] The imidazole derivatives of the present invention have the general formula:
wherein
each of R,, R2 and R3, which can be the same or different, is hydrogen, chloro, bromo, fluoro, methyl,
ethyl, methoxy, amino, hydroxy or nitro; R4 is hydrogen or an alkyl radical of 1 to 7 carbon atoms;
X is
R5 is hydrogen or hydroxy; and n is an integer from 1 to 4. The non-toxic pharmaceutically
acceptable add addition salts of these compounds are also within the scope of the
invention.
[0005] The compounds of the formula (I) form acid addition salts with both organic and inorganic
acids. They can thus form many pharmaceutically usable acid addition salts, such as,
for instance, chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates,
tartrates, maleates, citrates, benzoates, salicylates, ascorbates and the like.
[0006] The invention includes within its scope pharmaceutical compositions comprising at
least one of the compounds of formula (I) or a non-toxic, pharmaceutically acceptable
acid addition salt thereof, and a compatible pharmaceutically acceptable carrier therefor.
[0007] The present invention provides, for example, the following specific compounds of
formula (I) wherein X represents ―CHR
5― and R
5 is hydrogen:
4-[2-(2'-methylphenyl)-ethyl]-imidazole
4-[2-(3'-methylphenyl)-ethyl]-imidazole
4-[2-(4'-methylphenyl)-ethyl)-imidazole
4-[2-(2',3'-dimethylphenyl)-ethyl]-imidazole
4-[2-(2',8'-dimethylphenyl)-ethyl]-imidazole
4-[2-(2',4'-dimethylphenyl)-ethyl]-imidazole
4-[2-(2',5'-dimethylphenyl)-ethyl]-5-methyl-imidazole
4-[2-(2',5'-di methylphenyl)-ethyl]-imidazole
4-[2-(3',4'-dimethylphenyl)-ethyl]-imidazole
4-[2-(3',4'-dimethylphenyl)-ethyl]-5-methyl-imidazole
4-[2-(2',4',6'-trimethylphenyl)-ethyl]-imidazole
4-[2-(2'-ethylphenyl)-ethyl]-imidazole
4-[2-(2',6'-diethylphenyl)-ethyl]-imidazole
4-[2-(2'-methoxyphenyl)-ethyl]-imidazole
4-[2-(2'-chlorophenyl)-ethyl]-imidazole
4-[2-(3'-chlorophenyl)-ethyl]-imidazole
4-[2-(4'-chlorophenyl)-ethyl]-imidazole
4-[2-(2',6'-dichlorophenyl)-ethyl]-imidazole
4-[2-(2',3'-dichlorophenyl)-ethyl]-imidazole
4-[2-(2',6'-dibromophenyl)-ethyl]-imidazole
4-[2-(2',6'-difluorophenyl)-ethyl]-imidazole
4-[2-(2'-methylphenyl)-ethyl]-5-methyl-imidazole
4-[2-(2',6'-di methylphenyl)-ethyl]-5-methyl-imidazole
4-[3-(phenyl)-propyl]-imidazole
4-[3-(2'-methylphenyl)-propyl]-imidazole
4-[3-(3'-methylphenyl)-propyl]-imidazole
4-[3-(4'-methylphenyl)-propyl]-imidazole
4-[3-(2',3'-dimethylphenyl)-propyl]-imidazole
4-[3-(2',6'-dimethylphenyl)-propyl]-imidazole
4-[3-(2'-chlorophenyl)-propyl)-imidazole
4-[3-(2',6'-dichlorophenyl)-propyl]-imidazole
4-[4-(2'-methylphenyl)-butyl]-imidazole
4-[4-(3'-methylphenyl)-butyl]-imidazole
4-[4-(2',3'-dimethylphenyl)-butyl]-imidazole
4-[4-(2',6'-dimethylphenyl)-butyl]-imidazole
4-[4-(2',6'-dichlorophenyl)-butyl]-imidazole
4-[5-(2'-methylphenyl)-pentyl]-imidazole
4-[5-(2',6-dimethylphenyl)-pentyl]-imidazole
4-[5-(2',6'-dichlorophenyl)-pentyl]-imidazole
[0008] The following specific compounds of formula (I) wherein X represents ―CHR
5― and R
5 is hydroxy:
4-[2-(2'-methylphenyl)-1-hydroxyethyl]-imidazole
4-[2-(3'-methylphenyl)-1-hydroxyethyl]-i midazole
4-[2-(4'-methylphenyl)-1-hydroxyethyl]-imidazole
4-[2-(2',6'-dimethylphenyl)-1-hydroxyethyl]-imidazole
4-[2-(2',3'-dimethy)phenyl)-1-hydroxyethy)]-imidazo)e
4-[2-(2'-ethylphenyl)-1-hydroxyethyl]-imidazole
4-[2-(2',6'-diethylphenyl)-1-hydroxyethyl]-imidazole
4-[2-(2'-chlorophenyl)-1-hydroxyethylJ-imidazole
4-[2-(2',6'-dichlorophenyl)-1-hydroxyethyl]-imidazole
4-[2-(2',6'-dibromophenyl)-1-hydroxyethyl]-imidazole
4-[2-(2'-methylphenyl)-1-hydroxyethyl]-5-methyl-imidazole
4-[2-(2',6'-dimethylphenyl)-1-hydroxyethyl]-5-methyl-imidazole
4-(3-phenyl-1-hydroxypropyl)-imidazole
4-(3-(2'-methylphenyl)-1-hydroxypropyl]-imidazole
4-[3-(3'-methylphenyl)-1-hydroxypropyl]-imidazole
4-[3-(4'-methylphenyl)-1-hydroxypropyl]-imidazole
4-[3-(2',3'-dimethylphenyl)-1-hydroxypropyl]-imidazole
4-[3-(2',4'-dimethy)phenyt)-1-hydroxypropy)]-imidazole
4-[3-(2',6'-dimethylphenyl)-1-hydroxypropyl]-imidazole
4-(3-(2',6'-dimethylphenyl)-1-hydroxypropyl]-5-methyl-imidazole
4-[4-(2'-methylphenyl)-1-hydroxybutyl]-imidazole
4-[4-(2',4'-dimethylphenyl)-1-hydroxybutyl]-imidazole
4-[4-(2',6'-dimethylphenyl)-1-hydroxybutyl]-imidazole
4-[5-(2'-methylphenyl)-1-hydroxypentyl]-imidazole
4-[5-(2',6'-dimethylphenyl)-1-hydroxypentyl]-imidazole
4-[3-(2',4',6'-trimethylphenyl)-1-hydroxypropyl]-imidazole
4-[3-(4'-ethylphenyl)-1-hydroxypropyl]-imidazole
4-(2-phenyl-1-hydroxyethyl)-imidazole e
4-[4-(2',6'-dichlorophenyl)-1-hydroxybutyl]-imidazole
4-(2-(2',6'-dichlorophenyl)-1-hydroxyethyl]-5-methyl-imidazole
4-[2-(2'-chlorophenyl)-1-hydroxyethyl]-5-methyl-imidazole
4-[3-(2',3'-dimethylphenyl)-1-hydroxypropyl]-5-methyl-imidazole
4-(3-phenyl-1-hydroxypropyl)-5-methyl-imidazole
4-(2-phenyl-1-hydroxyethyl)-5-methyl-imidazole
4-[2-(2',3'-dimethylphenyl)-1-hydroxyethyl]-5-methyl-imidazole
4-[3-[4'-methylphenyl)-1-hydroxypropyl]-5-methyl-imidazole
4-[3-(3'-methylphenyl)-1-hydroxypropyl]-5-methyl-imidazole
4-[3-(4'-methoxyphenyl)-1-hydroxypropyl]-5-methyl-imidazole
4-[2-(2',5'-dimethylphenyl)-1-hydroxyethyl]-5-methyl-imidazole
4-[2-(3',4'-dimethylphenykl)-1-hydro xyethyt]-5-methy)-imidazole
and the following specific compounds of formula (I) wherein X represents
4-[2-(2',6'-dimethylphenyl)-1-oxoethyl]-imidazole
4-[2-(2',6'-dichlorophenyl)-1-oxoethyl]-imidazole
4-[2-(2',6'-dichtorophenyl)-1-oxoethyl]-5-methyl-imidazol
4-[3-(2'-methylphenyl)-1-oxopropyl]-imidazole
4-[2-(2'-chlorophenyl)-1-oxoethyl]-imidazole
4-[3-(2'-chlorophenyl)-1-oxopropyl]-imidazole
4-[3-(3'-methylphenyl)-1-oxopropyl]-imidazole
4-[3-(4'-methylphenyl)-1-oxopropyl]-imidazole
4-[3-(2',6'-dimethylphenyl)-1-oxopropyl]-imidazole
4-[3-(2',3'-dimethylphenyl)-1-oxopropyl]-imidazole
4-[5-(2',6'-dimethylphenyl)-1-oxopentyl]-imidazole
[0009] The compounds of the present invention have been found to possess excellent antihypertensive
properties. Preliminary tests have shown that they also possess other valuable pharmacological
properties, for example, β-blocking, antithrombotic and diuretic activity.
[0010] While all of the compounds of formula (I) have the aforementioned activities, certain
groups of compounds remain preferred. One such preferred group can be represented
by the structural formula:
wherein
R5 and n are the same as before; each of R'1, R'2 and R'3, is hydrogen, chloro, methyl, ethyl, methoxy or hydroxy; and R'4 is hydrogen or methyl. Particularly preferred antihypertensives are those compounds
of formula (II) above wherein R'1, R'2, R'3 and R'5 are the same as before and R'4 is hydrogen.
[0011] β-blocking activity has been found particularly in compounds of formula (II) above,
wherein R
5 is hydroxy, R'
1, R'
2 and R'
3 are as before and R'
4 is alkyl, preferably methyl.
[0012] Diuretic activity has been found particularly in compounds of formula (II), wherein
R
5 is hydroxy, R
1', R
2' and R
3' are as before and R
4' is hydrogen.
[0013] According to a feature of the invention, the compounds of formula (I) in which X
is ―CHOH― or ―CO― are made by a Grignard reaction in which an imidazole aldehyde of
the formula:
wherein
R4 is as defined before, is reacted with an arylalkyl magnesium halide derivative of
the formula:
wherein
R,, R2, R3, R4 and n are as defined before and Hal is a halogen atom. This reaction gives not only
the expected product in which X is -CHOH- but also the corresponding product in which
X is ―CO―.
[0014] The arylalkylmagnesium halide derivative can be, for example, an arylalkylmagnesiumbromide
derivative, which is prepared by reacting the corresponding arylalkylbromide derivative
with magnesium. Suitable solvents for the reaction include a variety of ethers, preferably
tetrahydrofuran. The arylalkylmagnesiumhalide derivative is prepared in the usual
way by adding the arylalkylmagnesiumhalide derivative in a suitable solvent, e.g.
tetrahydrofuran, dropwise onto magnesium turnings covered by tetrahydrofuran, at the
boiling point of the reaction mixture. When the magnesium turnings have reacted, the
mixture is cooled slightly and the 4-imidazole derivative is added in solid form in
small portions. After the addition, the reaction mixture is refluxed until all of
the 4-imidazole derivative has reacted. The reaction time varies between one and five
hours. In the reaction, at least two equivalents of arylalkylmagnesiumhalide are used
per one equivalent of 4-imidazolealdehyde, because the last mentioned compound contains
active hydrogen which binds a part of the Grignard reagent.
[0015] The above described Grignard reaction utilizing a 4-imidazolealdehyde as starting
material is a surprising and new method for the synthesis of imidazole derivatives.
The process is surprising in view of the teachings of the prior art. Thus, for example,
Deulofeu et al., J. Org. Chem., 1949, 915 states that 4-imidazolealdehyde does not
react with methylmagnesiumiodide, i.e., in the Grignard reaction.
[0016] It is further surprising that in the above described Grignard reaction a compound
of the formula (III)
wherein
R1, R2, R3' R4 and n are the same as before, is formed. The amount of the compound of the formula
(III), which can be isolated from the reaction mixture depends on the structure of
the derivative, the reaction time, and the amount of Grignard reagent used. Thus when
one and a half equivalents of a longer chained Grignard reagent are reacted with the
aldehyde derivative using relatively shorter reaction times than usually, from about
one half to two hours, the amount of the compound of formula (III) can be as high
as 50% of the isolated products.
[0017] Another process for the preparation of compounds of the present invention, in which
X is ―CHOH― comprises reducing a compound of the formula (III) to a compound of formula
(I) wherein X is -CHOH-. The reduction is performed by usual methods, for example
using sodium borohydride in ethanol.
[0018] A two-stage process for the preparation of compounds of the present invention wherein
X is ―CH
2― comprises a first stage wherein a compound of the formula (I) in which X is -CHOH-
is dehydrated to a compound of the formula (IV)
wherein
R1, R3, R3 and R4 are defined as before and n' is 0-3, and a second stage, wherein the compound of
the formula (IV) is hydrogenated to a compound of the formula (I) in which X is ―CHZ―.
[0019] The dehydration is preferably performed by refluxing in an appropriate acidic solution,
e.g. concentrated hydrochloric acid. In the second stage the hydrogenation is conveniently
carried out at room temperature with good stirring in the above mentioned acidic solution
in the presence of a catalyst in a hydrogen atmosphere. Suitable catalysts are for
example platinum oxide, palladium-on- carbon or Raney-nickel.
[0020] Yet another process for the preparation of the compounds of formula (I) in which
X is -CH
2- comprises reacting formamide with a benzene derivative of the formula:
wherein
R1, R2, R3 and n are as defined hereinabove, and Q is a radical of formula:
wherein
R Is a substituted and unsubstituted alkyl, arylalkyl or aryl group, and R4 and Hal are as defined hereinabove. Preferably the reaction is performed by vigorously
boiling the benzene derivative in formamide, the reaction time varying with the particular
material employed.
[0021] Reaction times typically are from 30 minutes to 8 hours. Obviously, the formamide
treatment will be followed by reaction with an appropriate acid (e.g. HCI) when Q
in the starting material is
In order to obtain the corresponding compound of formula (I).
[0022] Similarly, when a starting material wherein Q is
is employed, then the formamide treatment will be followed by hydrogenation, thus
affording the desired compound of formula (I).
[0023] A further process for the preparation of the compounds of the formula (I) in which
X is -CH
2- comprises hydrolysing a corresponding compound of the formula:
wherein
R1, R2' R3, R4 and n are as defined before and R6 is an alkyl group of 1 to 7 carbon atoms or an aryl radical of 6 to 10 carbon atoms.
Preferably, the hydrolysis is carried out by boiling the starting material, an N-acylated
imidazole derivative, in an aqueous solution of an inorganic acid until the reaction
is completed.
[0024] Yet another process for the preparation of the compounds of formula (I) in which
X is ―CH
2― , comprises hydrogenating a starting material of the formula:
or
.wherein
R1, R2, R3, R4, n and R6 are as defined before and R12 is an aryl group. The hydrogenation is conveniently conducted in the presence of
a suitable catalyst and under a hydrogen atmosphere, with stirring or using metallic
sodium in liquid ammonia. Suitable catalysts include platinum oxide, palladium-on
carbon and Raney nickel. Reaction temperatures vary with the particular starting material
employed, with typical temperatures being 25-70°C.
[0025] The present invention further provides yet another process for preparing compounds
of the invention in which R
4 is hydrogen and X is ―CH
2―. Thus, according to this embodiment of the invention, a starting material of the
formula V:
wherein
R1, R2, R3 and n are as hereinbefore defined; wherein R8, R9, R10 and R11, which can be the same or different, are each hydrogen, hydroxy, halogen, amino,
-0- alkyl of 1 to 7 carbon atoms or
wherein
R6 is defined as before; or wherein R8 and R10 can be combined to form an oxo group, or R9 and R11 can be combined to form an oxo group, or both R8 and R10 and R9 and R" can simultaneously form oxo groups; is reacted with a reagent capable of converting
said starting material to the corresponding imidazole of the formula:
wherein
R1, R2, R3 and n are defined as before. Reagents capable of converting the depicted starting
material to the corresponding imidazole include NH3 + CH20 (or a source of ammonia and formaldehvde); HN=CH―NH2;
and HCONH2. Choice of an appropriate reagent varies with the particular starting material employed.
For instance, when the starting material is a haloketone or a haloaldehyde, for example,
when Rs and R10 together form a keto group, Rg is bromine and R11 is hydrogen, or when Rg and R11 form a keto group, R8 is bromine and R10 is hydrogen, then it is preferable to react the starting material with formamide
in order to obtain the 4-arylalkylimidazole derivative.
[0026] It is likewise preferable to employ formamide as the reagent in cases where, in place
of the bromine atom in the aforementioned starting materials, there is instead a hydroxyl,
amino or acetyl group. In these instances, formamide is used in excess and acts in
part as the solvent. Generally, the reaction is run at the boiling point of formamide
for a period of time ranging from one to five hours.
[0027] If the starting material is a glyoxal derivative, e.g., benzyl glyoxal or other compound
of the type:
then the ammonia needed for the synthesis of the imidazole ring is suitably taken
from ammonium acetate, while the needed formalin is taken from hexamethylenetetramine;
two equivalents of these reagents are used per equivalent of glyoxal derivative. Suitable
solvents are, for example, dimethylformamide and formamide. Typically, the reaction
temperature is the boiling point of the reaction mixture, and the reaction time is
usually from one to three hours. Alternatively, the glyoxal derivative can be reacted
directly with ammonia and formaldehyde, or with formamide, but the yields of desired
product are generally lower.
[0028] A surprising aspect of the above mentioned reaction is the fact that the hydroxyacetal
starting materials, e.g., compounds of the formula:
very readily react with formamide to form the corresponding imidazoles (ref. example
35c).
[0029] As a variation of the above described process, a starting material of formula (V)
can be treated with an appropriate reagent, particularly formamide, under milder conditions
than those discussed above, allowing isolation of the intermediate oxazole, which
can then be further reacted with formamide to afford the corresponding compound of
formula (I).
[0030] In this variation, the first formamide treatment is carried out at a low temperature
(80―120°C, depending on the particular starting material employed), to afford an oxazole
of the formula:
which can then be easily reacted with formamide, typically at about 180°C, for about
4 hours, to afford the desired compound of the present invention.
[0031] Yet another method for the preparation of the compounds of formula (1) wherein X
is ―CH
2― comprises reacting a N-trialkylsilylimidazole of the formula
wherein
Y is an alkyl group, preferably methyl, with an arylalkylhalogenide of the formula
wherein
R" R2' R3 and n are as before and Hal is a halogen atom, in the presence of a Lewis acid, for
example titanium tetrachloride, aluminium chloride or zinc chloride. As solvent can
be used for example methylene chloride or chloroform. The reaction is preferably carried
out at room temperature stirring the starting materials for 6-12 hours.
[0032] The starting materials of formula (V) can be prepared by known methods. Reference
is made to Examples 35(a) and (b) set forth hereinafter for a description of methods
which have been employed to prepare various starting materials of formula (V), it
being understood that such examples are simply illustrative of procedures which can
be utilized to prepare the desired starting materials.
[0033] As stated herein above, the compounds of the general formula (I) and their non-toxic,
pharmaceutically acceptable acid addition salts have valuable pharmacological properties
and have been found to possess excellent anti-hypertensive activity in mammals. This
activity makes these imidazole derivatives particularly useful in the treatment of
high blood pressure.
[0034] Preliminary tests have shown that they also possess other pharmacological properties
as well, for example, A-blocking, antithrombotic and diuretic activity.
[0035] Administration of isomeric compounds of formula (I), their non-toxic pharmaceutically
acceptable acid salts or mixtures thereof may be achieved parenterally, intravenously
or orally. Typically, an effective amount of the derivative is combined with a suitable
pharmaceutical carrier. As used herein, the term "effective amount" encompasses those
amounts which yield the desired activity without causing adverse side-effects. The
precise amount employed in a particular situation is dependent upon numerous factors
such as method of administration, type of mammal, condition for which the derivative
is administered, etc., and of course the structure of the derivative.
[0036] One of the most potent anti-hypertensitve derivatives of the invention is 4-)2-(2',6'-dimethylphenyl)-ethyl]imidazole,
the daily dose of which, orally administered generally ranges from about 0.3-0.7 milligrams
per kilogram of mammal.
[0037] The pharmaceutical carriers which are typically employed with the derivatives of
the present invention may be solid or liquid and are generally selected with the planned
manner of administration in mind. Thus, for example, solid carriers include lactose,
sucrose, gelatin and agar, while liquid carriers include water, syrup, peanut oil
and olive oil. Other suitable carriers are well-known to those skilled in the art
of pharmaceutical formulations. The combination of the derivative and the carrier
may be fashioned into numerous acceptable forms, such as tablets, capsules, suppositories,
solutions, emulsions, and powders.
[0038] The anti-hypertensive properties of the imidazole derivatives of the present invention
have been determined by the following procedure. Sprague-Dawley rats of normal weight
were first anesthetized with urethane. After this, the femoral artery was connected
by way of a polyethylene tube with a blood pressure transducer. The test substance
was then injected into the femoral vein and the blood pressure and the pulse frequency
were registered with a recorder.
[0039] In a further test for anti-hypertensive properties unanesthetized Vistar spontaneous
hypertensive rats (SHR) were used. The test derivative was administered perorally
by way of a tube into the stomach. The blood pressure was measured from the tail using
an indirect bloodless method.
[0040] In another experiment 3 months old spontaneous hypertensive male rats were used to
test the anti-hypertensive properties during a period of 4 weeks. The test derivative
was administered daily to each rat in the drinking water and the blood pressure of
the tail was measured by a standard electric method.
[0041] In additional tests the anti-hypertensive effect was studied on dogs. In these tests
single doses were administered intravenously and the blood pressure was measured intra-arterially
and intravenously.
[0042] The β-blocking activity was measured in vitro as follows: The atrium of a guinea-pig
was isolated. The inhibiting activity of the compound against isoprenaline-induced
chronotropic and inotropic action in the isolated atrium was measured. The antithrombotic
activity was investigated in vitro. The inhibiting activity of the compounds against
ADP and collagen-induced aggregation of thrombocytes was measured. In the test thrombocytes
from a cow was used. To 1.2 ml of plasma containing 250000 thrombocytes/mm
3 were added 50 µl of a solution of the compound to be tested. After 10 min incubation
either ADP or collagen was added. The aggregation of the thrombocytes was turbidimetrically
determined at λ = 605 nm.
[0043] Acute toxicity was determined by using female mice of NMRI-Strain with an age of
about 7 months and weighing 30-40 g. The administration of the test compound was i.v.
[0044] Thus, 4-[2-(2',6'-dimethylphenyl)-ethyl]-imidazole, which has a LD
w value of 60 mg/kg i.v., was found in the blood pressure study with anesthetized rats
of normal weight described above to cause a registrable lowering of the blood pressure
with a dose of 30 µg/kg i.v.
[0045] With a dose of 100 µg/kg i.v. the blood pressure lowering was quite clear and with
a dose of 300 µg/kg i.v. the reduction of blood pressure was on an average 20 per
cent, the decrease of pulse frequency being 15 per cent on an average. The duration
of the effect was at least 60 minutes (after which time the determination was interrupted).
As the LD
50 is 60 mg/kg i.v. in mice, it can be concluded that the therapeutic range is very
broad. When the anti-hypertensive effect of the compound was determined with awake
SHR- rats, it was found that the decrease of blood pressure was about 15 per cent
with a dose of 3 mg/-kg p.o. and 20 per cent with a dose of 5 mg/kg p.o. one hour
after the administration. In the test for anti- hypertensive properties during a 4
weeks period with spontaneous hypertensive rats was found that with a dose of 250
µg/kg daily p.o. a significant reduction of blood pressure was achieved. In toxicological
experiments performed at the same time was found that a dose of 10 mg/kg daily of
the compound did not give any toxic symptoms. Also from these experiments can thus
be deduced that the therapeutic range of the compound is very broad.
[0046] Furthermore the reduction of the blood pressure in the performed test was observed
to be smooth and of long duration. In the tests with dogs was found that a dose of
30 µg/kg i.v. gave a 20 per cent long-lasting decrease of the blood pressure.
[0047] The compound 4-[2-(2'-methylphenyl)-ethyl]-imidazole, which has a LD
50 value of 50 mg/kg i.v. in mice, caused a blood pressure lowering of 25 per cent measured
one hour after the administration with a dose of 10 mg/kg p.o. The duration of the
effect was long-lasting, at least 6 hours (after which time the determination was
interrupted).
[0048] For the compound 4-[2-(2',6'-dichlorophenyl)-ethyl]-imidazole having a LDo of 50
mg/kg i.v. in mice the lowering of the blood pressure was 30 per cent measured 30
minutes after administration with a dose of 0.4 mg/kg i.v.
[0049] For the compound 4-[3-(2',6'-dimethylphenyl)-propyl]-imidazole having a LD
50 of 25 mg/kg i.v. in mice, the following results in the above mentioned tests were
obtained: lowering of blood pressure with a dose of 100 µg/kg i.v. of 13 per cent,
30 minutes after administration; lower of blood pressure with a dose of 10 mg/kg p.o.
of 18 per cent one hour after administration. The duration of the effect was long-lasting,
in the latter case for example at least 6 hours.
[0050] The compound 4-[4-(2',6'-dimethylphenyl)-butyl]-imidazole, having a LD
SO of 135 mg/kg i.v. in mice, produced a decrease in the blood pressure of about 10
per cent, with a dose of 10 mg/kg p.o. (one hour after administration).
[0051] For the compound 4-[2-(2'-chlorophenyl)-hydroxyethyl]-imidazole having a LD
50 of 110 mg/kg i.v. in mice, the lowering of blood pressure was 30 per cent, measured
30 minutes after administration with a dose of 0,7 mg/kg i.v.
[0052] For the compound 4-[2-(2',6'-dimethylphenyl)-hydroxyethyl]-imidazole having a LD
50 of 130 mg/kg i.v. in mice, the lowering of blood pressure was 25 per cent, measured
30 minutes after administration with a dose of 0.1 mg/kg i.v.
[0053] For the compound 4-[2-(2',6'-dimethylphenyl)-1-oxoethyl]-imidazole having a LD
SO of 150 mg/kg i.v. in mice, the lowering of blood pressure was 15 per cent, measured
one hour after administration with a dose of 20 mg/kg p.o.
[0054] The compound 4-[2-(2',3'-dimethylphenyl)-ethyl]-imidazole, which has a LD
50 value of 45 mg/kg i.v. in mice, caused a blood pressure lowering of 20 per cent measured
30 minutes after the administration with a dose of 1 mg/kg i.v. A pulse frequence
lowering of 20% was obtained 30 minutes after the administration of 3 mg/kg i.v.
[0055] The compound 4-[2-(2',6'-diethylphenyl)-ethyl]-imidazole which has a LD value of
60 mg/kg i.v. in mice caused a blood pressure lowering already with a dose of 0.03-0.1
mg/kg i.v. A blood pressure drop of 20% was measured 30 minutes after the administration
with a dose of 1-3 mg/kg i.v.
[0056] In the β-blocking activity test, the compound 4-[2-(2',6'-dichlorophenyl)-1-hydroxyethyl]-5-methylimidazole
caused at a concentration of 1 µg/ml a 68 per cent inhibition of isoprenaline induced
chronotropic effect and 59 per cent inhibition of isoprenaline induced inotropic effect.
The compound ws β
1-selective. LD
50 was 75 mg/kg in mice.
[0057] In the antithrombotic activity test, each of the compounds 4-[2-(2',6'-dimethylphenyl)-ethyl]-5-methylimidazole,
4-[2-(2',6'-dichlorophenyl)-1-hydroxyethyl]-5-methylimidazole and 4-[2-(2',6'-diethylphenyl)-ethyl]-imidazole
inhibited the collagen-induced aggregation of thrombocytes completely and the ADP-induced
aggregation clearly.
[0058] The compound 4-[2-(2',6'-dimethylphenyl)-1-hydroxyethyl]-imidazole gave in rats a
diuretic effect of 161 per cent (5 h after administration) at dose of 4 mg/kg i.p.
injection. Before the test the rats were fasting over night and got 10 ml water p.o.
immediately before the injection. This compound has proved to be effective in diuretic
tests with dogs, too.
[0059] In the Examples below, where 1
H―NMR spectrum shifts are presented, the NMR spectra were determined with a Perkin-Elmer
R 24 apparatus using an external tetramethylsilane standard, from which the presented
chemical shifts (8, ppm) are tabulated. The letters s, d, t and m are used to indicate
a singlet, doublet, triplet or multiplet, respectively. In the same connection, the
number of hydrogen atoms is also stated. The compounds which are indicated as bases
are tested in deuterium methanol, deuterium acetone or deuterium chloroform, while
the values for compounds which are indicated as hydrochlorides were determined in
deuterium oxide. The presented
13C―NMR-spectrum were determined with a Jeol FX-100 apparatus.
[0060] The mass-spectra were determined with a Perkin-Elmer RMU apparatus using direct inlet
system. The temperature employed was the lowest temperature needed for the evaporation
of the compound as base. In the examples the strongest and most essential fragment-ions
from a structural viewpoint are given as m/e values. In parenthesis is given the intensity
of the fragment-ion in relation to the main peak.
[0061] The following Examples 1 to 27 and 29 to 47 illustrate the invention.
Example 1
4-[3-(2',6'-dimethylphenyl)-1-hydroxypropyl]-imidazole
[0062] 4.8 g of dry magnesium turnings are covered with 100 ml of dry tetrahydrofuran (THF).
The mixture is heated to boiling and a solution of 42.6 g of 2-(2',6'-dimethylphenyl)-1-bromoethane
in 100 ml of dry tetrahydrofuran is added dropwise at such a rate that gentle refluxing
is maintained. After the addition is complete, the reaction mixture is refluxed for
an additional 30 minutes.
[0063] The reaction mixture is cooled to 50°C and 7.0 g of 4-imidazolealdehyde is added
slowly in small portions. After the addition is complete, the mixture is refluxed
for 5 hours. Then the reaction mixture is cooled and poured into 200 ml of cold water
containing 20 ml of concentrated hydrochloric acid. Part of the tetrahydrofuran is
distilled off to give a smaller volume and the tetrahydrofuran is replaced with water.
The mixture is washed twice with 50 ml portions of chloroform. The aqueous layer is
made alkaline with sodium hydroxide solution (pH about 8). The precipitate which forms
is washed with water and added to 100 ml of 4N NaOH solution and the mixture is stirred
vigorously for one hour. The precipitate is filtered, washed several times with water
and dried. The crude product is recrystallized from a mixture of water and ethanol
to give 10.1 g of a product melting at 157-158°C.
'H-NMR: 2.3 (m, 2H), 2.6 (s, 6H), 3.0 (m, 2H), 5.15 (t, 1 H), 5.45 (s, 2H) 7.25 (s,
3H), 7.35 (s, 1 H), 8.0 (s, 1 H)
MS: 230 (21%), 212 (20%), 197 (13%), 133 (11%), 124 (7%), 119 (18%), 118 (23%), 117
(18%), 115 (11%), 111 (98%), 98 (100%), 97 (69%), 95 (8%), 93 (7%), 91 (21%), 82 (27%),
81 (10%)
Example 2
4-[3-(2',6'-dimethylphenyl)-1-oxopropyl]-imidazole.
[0064] The method described in Example 1 is followed except that 9.6 g of 4-imidazolealdehyde
is used. The precipitate at pH about 8 is added to 4N sodium hydroxide solution and
the mixture is stirred vigorously for one hour and filtered. The filtrate is neutralized
with hydrochloric acid and the precipitate is filtered. The filter cake is washed
with water and dried. The yield of crude product is 9.5 g and melt at 132-148°C. The
product is converted to its hydrochloride in ethyl acetate. The melting point is 172-178°C.
'H-NMR (HCI-salt): 2.35 (s, 6H), 3.1 (s, 4H), 4.55 (s, 2H), 7.0 (s, 3H), 8.15 (s,
1 H), 8.55 (s, 1 H)
Example 3
4-[3-(2',6'-dimethylphenyl)-1-hydroxypropyl]-imidazole
[0065] 2.3 g of 4-[3-(2',6'-dimethylphenyl)-1-oxopropyl]-imidazole is dissolved in 20 ml
of ethanol. 1.0 g of sodium borohydride is added with stirring at room temperature.
After the addition the mixture is stirred for 4 hours at room temperature, then evaporated
to dryness. 30 ml of water is added to the residue and the resultant mixture is stirred
and cooled. The precipitate is filtered and washed with water. The yield is 2.1 g
of 4-[3-(2',6'-dimethylphenyl)-1-hydroxypropyl]-imidazole.
[0066] In the Examples 4-27 the procedure of Example 1 is repeated except that in place
of 2-(2',6'-dimethylphenyl)-1-bromoethane is used the corresponding (substituted phenyl)-1-bromoalkane
and in the Examples 13, 14, 16, 18, 19, 20 and 27 is used 5-methyl-4-imidazolealdehyde
in place of
4- imidazolealdehyde.
Example 4
4-[3-(2',4'-dimethylphenyl)-1-hydroxypropyl]-imidazole
[0067]
M.p. 70-74°C (from water-ethanol)
1H―NMR: 2.0 (m, 2H), 2.2 (s, 6H), 2.6 (m, 2H), 4.5 (t, 1 H), 5.2 (s, 2H), 6.9 (m, 4H),
7.6 (s, 1 H)
Example 5
4-( 1-hydroxy-3-phenylpropyl)-imidazole
[0068]
M.p. 144-146°C (from water). M.p. at the hydrochloride 153-155°C (from isopropanol).
1H―NMR 2.25 (m, 2H), 2.7 (m, 2H), 4.75 (t, 1H), 5.15 (s, 2H) 7.0 (s, 1H), 7.25 (s,
5H), 7.65 (s, 1H) MS: 202 (8%), 181 (13%), 183 (6%), 169 (3%), 156 (3%),115 (4%) 111
(10%), 98 (100%), 97 (76%), 91 (16%), 82 (7%)
Example 6
4-[3-(2',3'-dimethylphenyl)-1-hydroxypropyl]-imidazole
[0069]
M.p. 130―134°C
1H―NMR (HCl): 2.1 (m, 2H), 2.15 (s, 3H), 2.25 (s, 3H), 2.7 (m, 2H), 4.85 (t, 1 H),
5.1 (s, 2H), 6.95 (s, 3H), 7.4 (s, 1 H), 8.7 (s, 1 H)
Example 7
4-[3-(3'-methylphenyl)-1-hydroxypropyl]-imidazole
[0070]
M.p. 104-106°C
'H-NMR: 2.15 (m, 2H), 2.3 (s, 3H), 2.6 (m, 2H), 4.7 (t, 1H), 5.1 (s, 2H), 7.0 (m,
5H), 7.6 (s. 1H).
Example 8
4-[3-(4'-methylphenyl)-1-hydroxypropyl]-imidazole
[0071]
M.p. 120―124°C
'H-NMR: 2.2 (m, 2H), 2.3 (s, 3H), 2.65 (m, 2H), 4,75 (t, 1 H), 5.15 (s, 2H), 7.05
(m, 5H), 7.65 (s, 1 H).
Example 9
4-[3-(2'-methylphenyl)-1-hydroxypropyl]-imidazole
[0072]
M.p. of the hydrochloride 164-166°C (from isopropanol-ethylacetate)
1H―NMR (HCl-salt): 1.9 (m, 2H), 2.1 (s, 3H), 2.55 (m, 2H), 4.6 (s, 3H), 4.8 (t, 1 H),
7.0 (s, 4H), 7.2 (s, 1 H), 8.5 (s, 1 H).
Example 10
4-[5-(2',6-dimethyiphenyl)-1-hydroxypentyl]-imidazole
[0073]
M.p. 129-134°C
1H―NMR (trifluoroacetic acid is added): 1.2-1.9 (m, 6H), 2.5 (s, 6H), 4.3 (t, 1 H),
5.5 (s, 2H), 6.8 (s, 3H), 7.35 (s, 1 H), 8.65 (s, 1 H)
Example 11
4-[2-(2'-chlorophenyl)-1-hydroxyethyl]-imidazole
[0074]
M.p. of hydrochloride 164-167°C.
1H―NMR (trifluoroacetic acid is added): 3.85 (d, 2H), 5.1 (t, 1H), 5.5 (2H), 7.0 (s,
1H), 7.25 (m, 4H), 7.65 (s, 1 H)
Example 12
4-[2-(2',6'-dichlorophenyl)-1-hydroxyethyl]-imidazole
[0075]
Melting point 138-141 °C. Melting point of hydrochloride 201―203°C (from water)
1H―NMR (HCl-salt): 3.4 (d, 2H), 4.8 (s, 3H), 5.2 (t, 1H), 7.2 (s, 1H), 7.3 (s, 3H),
8.75 (s, 1H)
Example 13
4-[2-(2'-chlorophenyl)-1-hydroxyethyl]-5-methyl-imidazole
[0076] 1H―NMR (HCl-salt): 1.65 (s, 3H), 3.05 (d, 2H), 4.6 (s, 3H), 5.0 (t 1 H), 7.0 (m, 4H),
8.4 (s, 1 H)
Example 14
4-[2-(2',8'-dichlorophenyl)-1-hydroxyethyl]-5-methyl-imidazole
[0077]
M.p. of hydrochloride 193-195°C (from water)
1H―NMR: 1.5 (s, 3H), 3.3 (d, 2H), 4.3 (s, 2H), 5.1 (t, 1H), 7.0 (s, 3H), 8.4 (s, 1H)
Example 15
4-[2-(3'-methylphenyl)-1-hydroxyethyl]-imidazole
[0078]
M.p. of hydrochloride 142-145°C.
'H-NMR (HCI-salt): 2.2 (s, 3H), 3.05 (d, 2H), 4.65 (s, 3H), 5.05 (t, 1 H), 6.9-7.2
(m, 5H), 8.55 (s, 1 H).
Example 16
4-[3-(2',6'-dimethylphenyl)-1-hydroxypropyl]-5-methyl-imidazole
[0079]
M.p. of hydrochloride 166-168°C.
'H-NMR (HCI-salt): 2.1 (s, 6H), 2.25 (s, 3H), 4.8 (s, 3H), 6.8 (s, 3H), 8.6 (s, 1H)
Example 17
4-[2-(2',6'-dimethylphenyl)-1-hydroxyethyl)-imidazole
[0080]
Melting point of hydrochloride 179-181°C.
'H-NMR: 2.2 (s, 6H), 3.2 (d, 2H), 4.7 (s, 3H), 5.05 (t, 1 H), 7.1 (s, 3H), 7.2 (s,
1 H), 8.6 (s, 1 H).
Example 18
4-(3-phenyl-1-hydroxypropyl)-5-methyl-imidazole
[0081] M.p. of the base 134-136°C.
Example 19
4-[2-(2',3'-dimethylphenyl)-1-hydroxyethyl]-5-methyl-imidazole
[0082] M.p. of the base 167-171 °C, M.p. of the hydrochloride 173-175°C.
Example 20
4-(2-phenyl-1-hydroxyethyl)-5-methyl-imidazole
[0083] M.p. of the base 111-120°C. M.p. of the hydrochloride 154-156°C.
Example 21
4-[3-(2',4',6'-tri methylphenyl)-1-hydroxypropyl]-imidazole
[0084] M.p. of the hydrochloride 153-155°C (from isopropanol).
Example 22
4-[2-(4'-methylphenyl)-1-hydroxyethyl]-imidazole
[0085] M.p. of the base 152-154°C (from isopropanol).
Example 23
4-[3-(4'-ethylphenyl)-1-hydroxypropyl]-imidazole
[0086] M.p. of the hydrochloride 124-129°C (from ethylacetate).
Example 24
4-(2-phenyl-1-hydroxyethyl)-imidazole
[0087] M.p. of the base 155-157°C (from isopropanol).
Example 25
4-[4-(2',6'-dichlorophenyl)-1-hydroxybutyl]-imidazole
[0088] M.p. of the base 53-55°C.
Example 26
4-[2-(2'-methylphenyl)-1-hydroxyethyl]-imidazole
[0089] M.p. of the base 149―151°C (from isopropanol). M.p. of the hydrochloride 176-178°C
(from ethanol).
Example 27
4-[2-(2',6'-dimethylphenyl)-1-hydroxyethyl]-5-methyl-imidazole
[0090] M.p. of the hydrochloride 177-179°C.
Example 28
4-[3-(2',6'-dimethylphenyl)-1-propenyl)-i midazole
[0091] 10 g of 4-[3-(2'-6'-dimethylphenyl)-1-hydroxypropyl]-imidazole is refluxed in 100
ml of concentrated hydrochloric acid for 10 hours. After cooling, the solution is
extracted with chloroform. The combined chloroform extracts are washed with 10 per
cent sodium hydroxide solution, then with water, dried and evaporated to dryness.
[0092] The residue which is crude product is purified further by column chromatography using
a Merck's reversed phase column, eluting the column with methanol. The melting point
of the product is 162-168°C (as hydrochloride from ethyl acetate).
'H-NMR (HCI-salt): 1.9 (s, 6H), 3.1 (d, 2H), 4.65 (s, 2H), 5.5-6.1 (m, 2H), 6.5 (s,
1 H), 6.6 (s, 3H), 8.35 (s, 1 H)
Example 29
4-[3-(2',6'-dimethylphenyl)-propyl]-imidazole
[0093] 5 g of 4-[3-(2',6'-dimethylphenyl)-1-hydroxypropyl]-imidazole is refluxed for 5 hours
in 50 ml of cone. hydrochloric acid. The solution is cooled, 0.2 g of 10 per cent
palladium on carbon is added and the reaction mixture is stirred vigorously in hydrogen
atmosphere at room temperature for as long as hydrogen is consumed. The mixture is
then filtered and the filtrate is distilled to dryness. 50 ml of water is added and
the solution is extracted with chloroform. The chloroform extract is washed with water,
then with about 5 per cent sodium hydroxide solution and finally with water and evaporated
to dryness. The crude product is dissolved in toluene and HCI-ethyl acetate is added
to precipitate the product as hydrochloride. Yield 3.8 g (82 per cent); m.p. 185-187°C
(from water).
'H-NMR (HCI-salt): 1.3 (m, 2H), 1.9 (s, 6H), 2.3 (m, 4H), 4.6 (s, 2H) 6.6 (s, 3H),
6.65 (s, 1H), 8.6 (s, 1H).
MS: 214 (18%), 133 (7%), 119 (135), 117 (7%), 115 (6%), 105 (5%), 95 (90%), 91 (13%),
82 (100%), 81 (91%).
[0094] In the examples 30-34 the procedure of Example 29 is repeated except that in place
of a 4-[3-(2',6'-dimethylphenyl)-1-hydroxypropyl]-imidazole is used in the Examples
30-33 the corresponding 4-[(substituted-phenyl)-1-hydroxyalkyl]-imidazole and in the
Example 34 is used 4-[2-(2,6'-dimethylphenyl)-1-tiydroxyethyl)-5-methyl-imidazole.
Example 30
4-[3-(2',4'-dimethylphenyl)-propyl]-imidazole
[0095] 1H―NMR: 1.9 (m, 2H), 2.15 (s, 3H), 2.2 (s, 3H), 2.5 (m, 4H), 6.7-7.05 (m, 4H), 7.5
(s, 1 H), 11.9 (s, 1H)
Example 31
4-[3-(3'-methylphenyl)-propyll-imidazole
[0096] 1H―NMR: 2.0 (m, 2H), 2.2 (s, 3H), 2.55 (m, 4H), 6.75 (s, 1H), 7.0 (m, 4H), 7.5 (s,
1H), 11.7 (s, 1H)
Example 32
4-[3-(2',3'-dimethylphenyl)-propyll-imidazole
[0097] 'H-NMR: 2.0 (m, 2H), 2.1 (s, 3H), 2.2 (s, 3H), 2.6 (m, 4H), 6.8-7.1 (m, 4H), 7.5
(s, 1H), 13 (s, 1H)
Example 33
4-[5-(2',6'-dimethylphenyl)-pentyl]-imidazole
[0098] 1H―NMR: 1.45 (m, 6H), 2.2 (s, 6H), 2.55 (m, 4H), 6.7 (s. 1 H), 6.9 (s, 3H) 7.9 (s,
1 H), 11.8 (s, 1 H)
Example 34
4-[2-(2',6'-dimethylphenyl)-ethyl]-5-methyl-imidazole
[0099]
M.p. of the hydrochloride 244-247°C.
'H-NMR: 1.99 (s, 3H), 2.23 (s, 6H), 2.88 (t, 4H), 4.99 (s, 2H), 7.04 (s, 3H), 8.62
(s, 1 H)
4-[2-(2',6'-dlmethylphenyl)-ethyl]-imidazole Example 35
a) 2-(2',6'-dimethylphenyl)ethylglyoxal diethyl acetal
[0100] 9 g of magnesium turnings are covered with 400 ml of dry tetrahydrofuran and the
mixture is warmed to boiling. To that mixture is then added 2-(2',6'-dimethylphenyl)-1-bromoethane
at such a rate that a gentle boiling is maintained. When the magnesium turnings have
reacted the solution containing the Grignard reagent is cooled to room temperature.
The reaction mixture is then added dropwise, over a period of 3 hours, to a cooled
(0-5°C) solution of diethoxyacetic acid piperidinyl amide (80.8 g) in 200 ml of dry
tetrahydrofuran. After the addition is complete, the reaction mixture is stirred for
two hours at about 5°C. The mixture is then poured into a cold 2% sulfuric acid solution
(1000 ml). The solution is extracted with toluene and the combined toluene extracts
are washed with water and evaporated to dryness to give a residue of about 95 g. The
residue is distilled under reduced pressure. The forefraction distilling below 120°C/0.6
mmHg is discarded and the rest, about 66 g, is crude 2-(2',6'-dimethylphenyl)-ethylglyoxal
diethyl acetal, which is used without purification in step b)
b) 1,1-diethoxy-2-hydroxy-4-(2',6'-dimethylphenyl)-butane
[0101] 66 g of crude 2-(2'6'-dimethylphenyl)ethylglyoxal diethyl acetal is dissolved in
250 ml of ethanol and 5.0 g of sodium borohydride is added in small portions at a
temperature below 30°C. After the addition is complete, the mixture is stirred overnight
at room temperature. About 100 ml of ethanol is distilled off and 300 ml of water
is added. The solution is extracted with chloroform. The combined chloroform extracts
are washed with water, dried with sodium sulfate, and evaporated to dryness. The yield
is about 60 g of light reddish brown oil, which is used directly in step c).
c) 4-[2-(2',6'-dimethylphenyl)-ethylJ-imidazole
[0102] 6.0 g of the oil from the preceding step and 150 ml of formamide are combined and
stirred at 150°C while passing ammonia gas into the solution for 6 hours. The mixture
is cooled to room temperature and 400 ml of water is added. Concentrated hydrochloric
acid is added with cooling until the pH is 3--4.
[0103] The solution is washed with toluene, cooled and the pH is adjusted to 10-12 with
20% sodium hydroxide solution. The mixture is extracted with chloroform and the combined
chloroform extracts are extracted with 10% acetic acid solution. The combined acetic
acid extracts are made alkaline (pH 10-12) while cooling with 20% sodium hydroxide
solution. The product is extracted into chloroform, and the combined chloroform extracts
washed with water and dried with sodium sulfate. The solution is evaporated to dryness
to give 4-[2-(2',6'-dimethylphenyl)-ethyl]-imidazole base, about 24 g.
[0104] The hydrochloride is prepared by dissolving the base in ethyl acetate and adding
HCI-isopropanol until pH is about 4. The mixture is cooled and filtered and the filter
cake washed with a small amount of ethyl acetate. After recrystallisation from a small
amount of isopropanol the melting point is 201-204°C. The base is liberated from the
hydrochloride and has the melting point 117-118°C.
1H―NMR (HCl-salt): 1.9 (s, 6H), 2.6 (s, 4H), 4.95 (s, 2H), 6.6 (s, 3H), 6.95 (s, 1
H), 8.5 (s, 1 H).
13H―NMR (HCl-salt): 19.86 (g), 24.20 (t), 29.12 (t), 116.19 (d), 127.32 (d). 129.02
(d), 133.48 (d), 133.89 (s), 137.52 (s), 137.70 (s)
[0105] In the Examples 36-39 the procedure of Example 35 is repeated except that in place
of 2-(2',6'-dimethylphenyl)-1-bromoethane is used the appropriate (substituted-phenyl)-1-bromoalkane.
4-[2-(2'-methylphenyl)-ethyl]-imidazole Example 36
[0106]
Melting point of the hydrochloride 179-183°C (from isopropanol)
1H―NMR: 2.2 (s, 3H), 2.8 (s, 4H), 4.75 (s, 2H), 6.95 (s, 1 H), 7.0 (s, 4H) 8.45 (s,
1 H)
MS: 186 (75%), 185 (17%), 171 (22%), 157 (6%), 142 (6%), 115 (4%), 105 (47%), 104
(8%), 103 (5%), 95 (10%), 91 (4%), 82 (12%), 81 (100%)
Example 37
4-[2-(3'-methylphenyl)-ethylJ-imidazole
[0107]
M.p. 78―81°C.
1H―NMR (HCl-salt): 2.0 (s, 3H), 2.65 (s, 4H), 4.65 (s, 2H), 6.8 (m, 5H), 8.45 (s, 1
H).
Example 38
4-[2-(2',3'-dimethylphenyl)-ethyl]-imidazole
[0108]
M.p. 146-148°C (193-197°C as hydrochloride)
1H―NMR (HCl-salt): 2.0 (s, 3H), 2.05 (s, 3H), 2.75 (s, 4H), 4.7 (s, 2H) 6.75 (s, 3H),
6.91 (s, 1 H), 8.5 (s, 1H)
Example 39
4-[4-(2',6'-dimethylphenyl)-butyl]-imidazole
[0109]
M.p. of hydrochloride 154-162°C (from ethylacetate-isopropanol)
13H―NMR (HCl-salt): 1.2 (m, 4H), 1.9 (s, 6H), 2.2 (m, 4H), 4.65 (s,2H), 6.55 (s, 4H),
8.4 (s, 1H) 13H―NMR (HCl-salt): 20.33 (q), 24.67 (f), 28.89 (t), 29.00 (t), 29.77 (t), 115.37 (d),
126.21 (d), 128.73 (d), 133.59 (d), 134.30 (s), 136.52 (s), 139.80 (s).
Example 40
4-[2-(2',6'-dimethylphenyl)-ethyl]-imidazole
[0110] A mixture of 13.0 g of 1-(2',6'-dimethylphenyl)-4-chloro-3,4-epoxybutane and 30 ml
of formamide is refluxed for 30 hours. The excess of formamide is distilled off and
20 ml of water is added. The mixture is then made alkaline with sodium hydroxide and
extracted with toluene. The combined toluene extracts are washed with water, then
with dilute hydrochloric acid. The combined hydrochloric acid extracts are made alkaline
with sodium hydroxide and the mixture is extracted with toluene. The toluene extracts
are washed with water and evaporated to dryness.
[0111] The residue, which is crude 4-[2-(2',6'-dimethylphenyl)-ethyl]-imidazole is transformed
to the hydrochloride in ethylacetate by adding an isopropanol solution containing
dry hydrogen chloride. The melting point of the hydrochloride is 198-202°C.
Example 41
4-[2-(2',3'-dimethylphenyl)-ethyl]-imidazole
[0112] A mixture of 10.0 g of 4-[(2',3'-dimethylphenyl)-ethyl]-N-acetylimidazole and 50
ml of 6N hydrochloric acid is refluxed with stirring for 6 hours. The mixture is distilled
to a smaller volume and 50 ml of water is added. The pH is adjusted with sodium hydroxide
to 8-9. The precipitate is filtered and washed with water. The product melts at 146°C.
Example 42
4-[3-(2',6'-dimethylphenyl)-propyl]-imidazole
[0113] 10 g 4-[1-chloro-3-(2',3'-dimethylphenyl)-propyl]-imidazole is dissolved in 80 ml
of ethanol. 0.1 g of 10% palladium on carbon is added and the reaction mixture is
stirred at room temperature in a hydrogen atmosphere until no more hydrogen is consumed.
The mixture is then filtered and the filtrate is evaporated to dryness. The residue
is dissolved in 30 ml of concentrated hydrochloric acid and the solution is cooled.
The precipitate is filtered and washed with a little amount of cold water. The product
is obtained in the form of the hydrochloride and melts at 185-187°C.
Example 43
4-[2-(2',3'-dimethylphenyl)-ethyl]-imidazole
[0114] 10 g of 4-[2-(2',3'-dimethylphenyl)-ethyl]-N-benzyl-imidazole is dissolved in 200
ml of ethanol. 0.2 g of 10% palladium on carbon is added and the reaction mixture
is stirred vigorously at 70°C in a hydrogen atmosphere until the uptake of hydrogen
ceases. The mixture is cooled and filtered. The filtrate is evaporated to dryness.
[0115] The residue is dissolved in ethylacetate and isopropanol containing dry hydrogen
chloride and added until the solution is slightly acidic. The precipitate is filtered
and washed with acetate. The hydrochloride of the product melts at 146-148°C.
[0116] In the examples 44-46 the procedure of Example 1 is repeated, except that in place
of 2-(2',6'-. dimethylphenyl)-1-bromoethane is used the corresponding (substituted
phenyl)-1-bromoalkane and in place of 4-imidazolealdehyde is used 5-methyl-4-imidazolealdehyde.
Example 44
4-(2-(2',5'-dimethylphenyl)-1-hydroxyethyl]-5-methyl-imidazole.
[0117] M.p. of the hydrochloride 169-170°C.
Example 45
4-[2-(3',4'-dimethylphenyl)-1-hydroxyethyl]-5-methyl-imidazole.
[0118] M.p. of the hydrochloride 161-163°C.
Example 46
4-(3-(4'-methylphenyl)-1-hydroxypropyl]-5-methyl-imidazole
[0119] M.p. of the hydrochloride 144-145°C.
Example 47
4-[2-(2',5'-dimethylphenyl)-ethyl]-5-methyl-imidazole
[0120] The procedure of Example 29 is repeated except that in place of 4-[3-(2',6'-dimethylphenyl)-1-hydroxypropyl]-imidazole
is used 4-[2-(2',5'-dimethylphenyl)-1-hydroxyethyl]-5-methyl-imidazole. M.p. of the
hydrochloride is 190-192°C.
Revendications pour l'(les) Etat(s) contractant(s) suivant(s) : BE CH DE FR GB IT
LI LU NL SE
1. Imidazole substitué de formule:
dans laquelle chacun des R
1, R
2 et R
3, qui peuvent être identiques ou différents, est de l'hydrogène, un groupe chloro,
bromo, fluoro, méthyle, éthyle, méthoxy, amino, hydroxyle ou nitro; R
4 est de l'hydrogèe ou un radical alkyle ayant 1 à 7 atomes de carbone; X est
R
s est de l'hydrogène ou un groupe hydroxyle, et n est un nombre entier de 1 à 4, à
condition que lorsque n est 1, et que X est -CH
2-, R
1, R
2, R
3 et R
4 ne soient pas tous de l'hydrogène, et que lorsque n est 1, X est ―CH
2―, deux des R,, R
2 et R
3 sont des groupes méthoxy, et le troisième est de l'hydrogène, R
4 ne soit pas un groupe méthyle; et ses sels d'addition avec un acide, pharmaceutiquement
acceptables, non toxiques.
2. Composé selon la revendication 1, dans lequel chacun des R1, R2 et R3, qui peuvent être identiques ou différents, est de l'hydrogène, un groupe chloro,
méthyle, éthyle, méthoxy ou hydroxyle.
3. Composé selon les revendications 1 ou 2, dans lequel R4 est de l'hydrogène ou un groupe méthyle.
4. 4-[2-(2',6'-diméthylphényl)-1-hydroxy-éthyl]-imidazole et ses sels d'addition avec
un acide, pharmaceutiquement acceptables, non toxiques.
5. 4-[2-(2',6'-dichlorophényl)-1-hydroxyéthyl]-5-méthyl-imidazole et ses sels d'addition
avec un acide, pharmaceutiquement acceptables, non toxiques.
6. 4-[2-(2',6'-diméthylphényl)-1-hydroxyéthyl]-5-méthyl-imidazole et ses sels d'addition
avec un acide, pharmaceutiquement acceptables, non toxiques.
7. 4-[2-(2-(2'-méthylphényl)-éthyl]-imidazole et ses sels d'addition avec un acide,
pharmaceutiquement acceptables, non toxiques.
8. 4-[2-(2',3'-diméthylphényl)-éthyl]-imidazole et ses sels d'addition avec un acide,
pharmaceutiquement acceptables, non toxiques.
9. 4-[2-(2',6'-diméthylphényl)-éthyl]-imidazole et ses sels d'addition avec un acide,
pharmaceutiquement acceptables, non toxiques.
10. 4-[3-(2',6'-diméthylphényl)-propyl]-imidazole et ses sels d'addition avec un acide,
pharmaceutiquement acceptables, non toxiques.
11. 4-[4-12',6'-diméthylphényl)-butyl]-imidazole et ses sels d'addition avec un acide,
pharmaceutiquement acceptables, non toxiques.
12. 4-[2-(2',6'-dichlorophényl)-éthyl-imidazole et ses sels d'addition avec un acide,
pharmaceutiquement acceptables, non toxiques.
13. 4-[2-l2',6'-diméthylphényl)-1-oxopropyl]- imidazole et ses sels d'addition avec
un acide, pharmaceutiquement acceptables, non toxiques.
14. 4-[2-(2',6'-diéthylphényl)-éthyl]-imidazole et ses sels d'addition avec un acide,
pharmaceutiquement acceptables, non toxiques.
15. 4-[2-(2'-chlorophényl)-1-hydroxyéthyl]-imidazole et ses sels d'addition avec un
acide, pharmaceutiquement acceptables non toxiques.
16. Procédé pour la préparation d'un composé comme revendiqué dans la revendication
1, dans lequel X est ―CHOH― et/ou -CO- qui consiste à faire réagir un imidazolealdéhyde
de formule:
dans laquelle R
4, est comme défini dans la revendication 1, avec un halogénure d'arylalkylmagnésium
de formule:
dans laquelle R
1, R
2 et R
3 sont comme défini dans la revendication 1, et Hal est un atome d'halogène.
17. Procédé pour la préparation d'un composé comme revendiqué dans la revendication
1, dans lequel X est -CHOH- qui consiste à réduire un composé de formule:
dans laquelle R
1, R
2, R
3, R
4 et n sont comme défini dans la revendication 1.
18. Procédé pour la préparation d'un composé comme revendiqué dans la revendication
1, dans lequel X est ―CH
2― qui consiste à hydrogéner un composé de formule:
dans laquelle R
1, R
2, R
3 et R
4 sont comme défini dans la revendication 1, et n' est zéro ou un nombre entier de
1 3.
19. Procédé pour la préparation d'un composé comme revendiqué dans la revendication
1, dans laquer X est ―CH
2― qui consiste à faire réagir le formamide avec un composé de formule:
dans laquelle R
1, R
2, R
3 et n sont comme défini dans la revendication 1, et Q est:
(dans lequel Hal est un atome d'halogène, R
4 est de l'hydrogène ou un groupe méthyle, et R est un groupe alkyle substitué ou non
substitué, aralkyle ou aryle) à condition que:
a) quand Q est
la réaction avec le formamide soit suivie par un traitement du produit intermédiaire
avec un acide; et
b) quand Q est
la réaction avec le formamide soit suivie par l'hydrogénation du produit intermédiaire.
20. Procédé pour la préparation d'un composé comme revendiqué dans la revendication
1, dans lequel X est ―CH
2―, qui consiste à hydrolyser un composé de formule:
dans laquelle R
1, R
2, R
3, R
4 et n sont comme défini dans la revendication 1, et R
6 est un radical alkyle ayant 1 à 7 atomes de carbone ou un radical aryle ayant 6 à
10 atomes de carbone.
21. Procédé pour la préparation d'un composé comme revendiqué dans la revendication
1, dans lequel X est -CH
2-, qui consiste à hydrogéner un composé de formules:
dans lesquelles R
1, R
2, R
3, R
4, et n sont comme défini dans la revendication 1, R
6 est un radical d'alkyle ayant 1 à 7 atomes de carbone ou un radical aryle ayant 6
à 10 atomes de carbone, et R
12 est un groupe aryle.
22. Procédé pour la preparation d'un composé comme revendiqué dans la revendication
1, dans lequel R
4 est de l'hydrogène, et X est ―CH
2―, qui consiste à faire réagir une matière de départ de formule:
dans laquelle R
8, Rg, R
10 et R
11, qui peuvent être identiques ou différents, sont chacun de l'hydrogène, un groupe
hydroxyle, halogéno, amino, -O-alkyle contenant 1 à 7 atomes de carbone ou
(dans lequel R
6 est un radical alkyle contenant 1 à 7 atomes de carbone ou un radical aryle contenant
6 à 10 atomes de carbone); ou bien dans laquelle R
s et R
10 peuvent être combinés pour former un groupe oxo, ou bien R
9 et R
11 peuvent être combinés pour former un groupe oxo, ou bien à la fois R
8 et R,
o, et Rg et R
11 peuvent former simultanément des groupes oxo, avec un réactif capable de transformer
ladite matière de départ en l'imidazole correspondant, et qui est une source d'ammonium
et de formaldéhyde; HN=CH―NH
2 HCOO- NH
4+, ou HCONH
2.
23. Procédé pour la préparation d'un composé comme revendiqué dans la revendication
1, dans lequel R
4 est de l'hydrogène et X est ―CH
2―, qui consiste à faire réagir une matière de départ de formule:
dans laquelle chaque groupe alkyle contient 1 à 7 atomes de carbone, et R
1, R
2 et R
3 sont comme défini dans la revendication 1, avec le formamide pour former l'imidazole
correspondant.
24. Procédé pour la préparation d'un composé comme revendiqué dans la revendication
1, dans lequel R
4 est de l'hydrogène et X est ―CH
2―, qui consiste à faire réagir le formamide avec un oxazole de formules:
dans lesquelles R
1, R
2, R
3 et n sont comme défini dans la revendication 1.
25. Procédé pour la préparation d'un composé comme revendiqué dans la revendication
1, dans lequel X est -CH
2- qui consiste à faire réagir un N-trialkylsilylimidazole de formule:
dans laquelle Y est un groupe alkyle, avec un halogénure d'arylalkyle de formule:
dans laquelle R
1, R
2' R
3 et n sont comme défini dans la revendication 1, et Hal est un atome d'halogène, en
présence d'un acide de Lewis.
26. Composition pharmaceutique comprenant un 4-aryl'alkylimidazole de formule générale:
dans laquelle chacun des R
1, R
2 et R
3, qui peuvent être identiques ou différents, est de l'hydrogène, un groupe chloro,
bromo, fluoro, méthyle, éthyle, méthoxy, amino, hydroxyle ou nitro; R
4 est de l'hydrogène ou un radical alkyle ayant 1 à 7 atomes de carbone; X est:
R
s est de l'hydrogène ou un groupe hydroxyle; et n est un nombre entier de 1 à 4, ou
bien un sel d'addition avec un acide, pharmaceutiquement acceptable, non toxique de
ce composé, en association avec un véhicule compatible, pharmaceutiquement acceptable,
et sous la forme d'un comprimé, d'un cachet, d'un suppositoire, d'une solution stérile,
d'une émulsion ou d'une poudre.
27. Composition comme revendiquée dans la revendication 26, dans laquelle le véhicule
est un produit solide.
28. Imidazole substitué comme défini dans la revendication 26, ou un sel d'acide pharmaceutiquement
acceptable, non toxique, de ce composé pour être utilisé en thérapie dans le traitement
de l'hyper-tension.
29. Imidazole substitué en position 4- comme revendiqué dans la revendication 1, pour
être utilisé en thérapie, comme un agent agissant contre la thrombose.
30. Imidazole substitué en position 4- comme revendiqué dans l'une quelconque des
revendications 4 à 15, ou un sel d'addition avec un acide, pharmaceutiquement acceptable,
non toxique, de ce composé, pour être utilisé en thérapie dans le traitement de l'hyper-tension.
31. 4-arylalkylimidazole comme défini dans la revendication 26, dans laquelle X est
R
4 est un groupe alkyle; et R
1, R
2, R
3 et n sont comme défini dans la revendication 26, et ses sels d'addition avec un acide,
pharmaceutiquement acceptables, non toxiques pour être utilises en thérapie comme
agents de β-blocage.
Patentansprüche für folgende(n) Vertragsstaat(en) : BE CH DE FR GB IT LI LU NL SE
1. Substituiertes Imidazol der Formel
worin jedes R
1, R
2 und R
3, das gleich oder verschieden sein kann, Wasserstoff, Chlor, Brom, Fluor, Methyl,
Ethyl, Methoxy, Amino, Hydroxy oder Nitro bedeutet; R
4 Wasserstoff oder einen Alkylrest mit 1 bis 7 Kohlenstoffatomen bedeutet;
darstellt, wobei R
5 Wasserstoff oder Hydroxy bedeutet; und n eine ganze Zahl von 1 bis 4 bedeutet, mit
dem Proviso, dass wenn n 1 und X ―CH
2― ist, R,, R
2, R
3 und R
4 nicht alle Wasserstoff sind und dass dann, wenn n 1, X ―CH
2―, zwei von R
1, R
2 und R
3 Methoxy und das dritte Wasserstoff bedeuten, R
4 nicht Methyl ist; sowie die nicht-toxischen pharmazeutisch annehmbaren Säureadditionssalze.
2. Verbindung gemäss Anspruch 1, dadurch gekennzeichnet, dass jedes R1, R2 und R3, das gleich oder verschieden sein kann, Wasserstoff, Chlor, Methyl, Ethyl, Methoxy
oder Hydroxy bedeutet.
3. Verbindung gemäss Anspruch 1 oder 2, dadurch gekennzeichnet, dass R4 Wasserstoff oder Methyl bedeutet.
4. 4-[2-(2',6'-Dimethylphenyl)-1-hydroxyethyl]-imidazol und dessen nicht-toxischen,
pharmazeutisch annehmbaren Säureadditionssalze.
5. 4-[2-(2',6'-Dichlorophenyl)-1-hydroxyethyl]-5-methyl-imidazol und dessen nicht-toxischen,
pharmazeutisch annehmbaren Säureadditionssalze.
6. 4-[2-(2',6'-Dimethylphenyl)-1-hydroxyethyl]-5-methyl-imidazol und dessen nicht-toxischen,
pharmazeutisch annehmbaren Säureadditionssalze.
7. 4-[2-(2'-Methylphenyl)-ethyJ]-imidazol und dessen nicht-toxischen, pharmazeutisch
annehmbaren Säureadditionssalze.
8. 4-[2-(2',3'-Dimethylphenyl)-ethyl]-imidazol und dessen nicht-toxischen, pharmazeutisch
annehmbaren Säureadditionssalze.
9. 4-[2-(2',6'-Dimethylphenyl)-ethyl]-imidazol und dessen nicht-toxischen, pharmazeutisch
annehmbaren Säureadditionssalze.
10. 4-[3-(2',6'-Dimethylphenyl)-propyl]-imidazol und dessen nicht-toxischen, pharmazeutisch
annehmbaren Säureadditionssalze.
11. 4-[4-(2',6'-Dimethylphenyl)-butyl]-imidazol und dessen nicht-toxischen, pharmazeutisch
annehmbaren Säureadditionssalze.
12. 4-[2-(2',6'-Dichlorophenyl)-ethyl]-imidazol und dessen nicht-toxischen, pharmazeutisch
annehmbaren Säureadditionssalze.
13. 4-[2-(2',6'-Dimethylphenyl)-1-oxopropyl]-imidazol und dessen nicht-toxischen,
pharmazeutisch annehmbaren Säureadditionssalze.
14. 4-[2-(2',6'-Diethylphenyl)-ethyl]-imidazol und dessen nicht-toxischen, pharmazeutisch
annehmbaren Säureadditionssalze.
15. 4-[2-(2'-Chlorophenyl)-1-hydroxyethyl]-imidazol und dessen nicht-toxischen, pharmazeutisch
annehmbaren Säureadditionssalze.
16. Verfahren zur Herstellung einer Verbindung gemäss Anspruch 1, worin X ―CHOH― und/oder
--CO- bedeutet, dadurch gekennzeichnet, dass man einen Imidazolaldehyd der Formel
worin R
4, die in Anspruch 1 angegebene Bedeutung hat, mit einem Arylalkylmagnesiumhalogenid
der Formel
worin R
1, R
2 und R
3 die in Anspruch 1 angegebenen Bedeutungen haben und Hal ein Halogenatom bedeutet,
umsetzt.
17. Verfahren zur Herstellung einer Verbindung gemäss Anspruch 1, worin X -CHOH- bedeutet,
dadurch gekennzeichnet, dass man eine Verbindung der Formel
worin R
1, R
2, R
3, R
4 und n die in Anspruch 1 angegebenen Bedeutungen haben, reduziert.
18. Verfahren zur Herstellung einer Verbindung gemäss Anspruch 1, in welcher X ―CH
2― bedeutet, dadurch gekennzeichnet, dass man eine Verbindung der Formel
worin R
1, R
2, R
3 und R
4 die in Anspruch 1 angegebenen Bedeutungen haben und n' 0 oder eine ganze Zahl von
1 bis 3 bedeutet, hydriert.
19. Verfahren zur Herstellung einer Verbindung gemäss Anspruch 1, in welcher X -CH2
bedeutet, dadurch gekennzeichnet, dass man Formamid mit einer Verbindung der Formel
worin R
1, R
2, R
3 und n die in Anspruch 1 angegebenen Bedeutungen haben und Q
bedeutet, (worin Hal ein Halogenatom, R
4 Wasserstoff oder Methyl und R eine substituierte oder unsubstituierte Alkyl-, Aralkyl-
oder Arylgruppe bedeuten) umsetzt, mit dem Proviso, dass:
ist, anschliessend an die Umsetzung mit Formamid die Behandlung des Zwischenproduktes
mit einer Säure erfolgt, und
bedeutet, anschliessend an die Umsetzung mit Formamid die Hydrierung des Zwischenproduktes
erfolgt.
20. Verfahren zur Herstellung einer Verbindung gemäss Anspruch 1, worin X -CH
2- bedeutet, dadurch gekennzeichnet, dass man eine Verbindung der Formel
worin R
1, R
2, R
3, R
4 und n die in Anspruch 1 angegebenen Bedeutungen haben und R
6 einen Alkylrest mit 1 bis 7 Kohlenstoffatomen oder einen Arylrest mit 6 bis 10 Kohlenstoffatomen
bedeutet, hydrolysiert.
21. Verfahren zur Herstellung einer Verbindung gemäss Anspruch 1, worin X -CH2- bedeutet,
dadurch gekennzeichnet, dass man eine Verbindung der Formel
oder
worin R
1, R
2, R
3, R
4 und n die in Anspruch 1 angegebenen Bedeutungen haben, R
6 einen Alkylrest mit 1 bis 7 Kohlenstoffatomen oder einen Arylrest mit 6 bis 10 Kohlenstoffatomen
und R
12 eine Arylgruppe bedeuten, hydriert.
22. Verfahren zur Herstellung einer Verbindung gemäss Anspruch 1, worin R
4 Wasserstoff und X ―CH
2― bedeutet, dadurch gekennzeichnet, dass man ein Ausgangsmaterial der Formel
worin R
8, R
9, R
10 und R
11, die gleich oder verschieden sein können und jeweils Wasserstoff, Hydroxy, Halogen,
Amino, -0-Alkyl enthaltend 1 bis 7 Kohlenstoffatome oder
(worin R
6 einen Alkylrest mit 1 bis 7 Kohlenstoffatomen oder einen Arylrest mit 6 bis 10 Kohlenstoffatomen
bedeutet) bedeuten; oder worin R
8 und R
10 unter Ausbildung einer Oxogruppe kombiniert sind oder R
9 und R
11 unter Ausbildung einer Oxogruppe kombiniert sind oder worin, sowohl R
8 und R
10 und R
9 und R
11 gleichzeitig Oxogruppen bilden, mit einem Reagens, das in der Lage ist, das Ausgangsmaterial
in das entsprechende Imidazol zu überführen und das eine Quelle für Ammoniak und Formaldehyd,
HN=CH-NH
2, HCOO- NH
+4 oder HCONH
2 ist, umsetzt.
23. Verfahren zur Herstellung einer Verbindung gemäss Anspruch 1, worin R
4 Wasserstoff und X -CH
2- bedeutet, dadurch gekennzeichnet, dass man ein Ausgangsmaterial der Formel
worin die Alkylgruppen jeweils 1 bis 7 Kohlenstoffatome enthalten und R
1, R
2 und R
3 die in Anspruch 1 angegebenen Bedeutungen haben, mit Formamid unter Bildung des entsprechenden
Imidazols umsetzt.
24. Verfahren zur Herstellung einer Verbindung gemäss Anspruch 1, worin R
4 Wasserstoff und X ―CH
2― bedeutet, dadurch gekennzeichnet, dass man Formamid mit einem Oxazol der Formel
worin R
1, R
2, R
3 und n die in Anspruch 1 angegebenen Bedeutungen haben, umsetzt.
25. Verfahren zur Herstellung einer Verbindung gemäss Anspruch 1, worin X ―CH
2― bedeutet, dadurch gekennzeichnet, dass man N-Trialkylsilylimidazol der Formel
worin Y eine Alkylgruppe bedeutet, mit einem Arylalkylhalogenid der Formel
worin R
1, R
2, R
3 und n die in Anspruch 1 angegebenen Bedeutungen haben und Hal ein Halogenatom ist,
in Gegenwart einer Lewis-Säure umsetzt.
26. Pharmazeutische Zusammensetzung, enthaltend ein 4-Arylalkylimidazol der allgemeinen
Formel
worin jedes R , R und R
3, das gleich oder verschieden sein kann, Wasserstoff, Chlor, Brom, Fluor, Methyl,
Ethyl, Methoxy, Amino, Hydroxy oder Nitro bedeutet, R
4 Wasserstoff oder einen Alkylrest mit 1 bis 7 Kohlenstoffatomen bedeutet, X
wobei R
5 Wasserstoff oder Hydroxy bedeutet, ist und n eine ganze Zahl von 1 bis 4 bedeutet,
oder ein nicht-toxisches pharmazeutisch annehmbares Säureadditionssalze davon zusammen
mit einem verträglichen, pharmazeutisch annehmbaren Träger und in Form einer Tablette,
Kapsel, von Suppositorien, einer sterilen Lösung, einer Emulsion oder eines Pulvers.
27. Zusammensetzung gemäss Anspruch 26, dadurch gekennzeichnet, dass der Träger fest
ist.
28. Substituiertes Imidazol gemäss Anspruch 26 oder ein nicht-toxisches, pharmazeutisch
annehmbares Säureadditionssalz davon, für die Verwendung bei der Therapie der Behandlung
von Hypertension.
29. 4-substituiertes imidazol gemäss Anspruch 1 für die Verwendung bei der Therapie
als antithrombotisches Mittel.
30. 4-substituiertes imidazol gemäss einem der vorhergehenden Ansprüche 4 bis 15 oder
ein nichttoxisches, pharmazeutisch annehmbares Säureadditionssalze davon, für die
Therapie bei der Behandlung von Hypertension.
31. 4-Arylalkyllmidazol gemäss Anspruch 26, worin
R
4 Alkyl ist und R
1, R
2, R
3 und n die in Anspruch 26 angegebenen Bedeutungen haben und dessen nichttoxische,
pharmazeutisch annehmbare Säureadditionssalze für die Verwendung in der Therapie als
β-Blockierungsmittel.